Advances in the Treatment of FLT3-Mutated AML
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2017, Vol 1, Issue 1
Abstract
AML is a heterogeneous disease and is the most common acute leukemia in adults. It has an annual US incidence over 20,000 and death rate of over 10,000 per year. The 5-year remission rates after conventional induction therapy is 40% below 60 years and 10%-20% in older patients. FLT3-ITD mutation has been added to the WHO risk stratification as a predictor of poor prognosis. On April 28, 2017 FDA approved midostaurinin combination with standard cytarabine and daunorubicin induction and cytarabine consolidation for treating adult newly diagnosed AML patients who are FLT3 mutation positive as detected by an FDA approved test. The FLT3 gene is located on chromosome 13q12, and the resultant protein is a member of the class III RTK family. The FLT3 RTK expression is normally limited to early myeloid progenitors and it appears to play a key role in the differentiation and maturation of hematopoietic precursors. FL binding to the receptor activates downstream signaling cascades, which mediate differentiation and growth. These pathways include the key intermediary proteins RAS, MEK, PI3K, AKT, and STAT-5 [1]. Over expression of FLT3 in cell lines results in increased pro¬liferation and decreased apoptosis [2]. FLT3 mutations occur as secondary events during AML clonal evolution [3] in approximately 30% of AMLs. In 23%, the mutations occur via ITD in the juxtamembrane domain and in 7% via point mutation usually in the Asp835 residue within the activation loop. Both muta¬tions result in constitutive activation of the kinase [2]. FLT3/ITD AML frequently presents with leukocytosis and normal cytogenetics and is more likely to arise de novo rather than out of an antecedent disorder such as MDS or a myeloproliferative neoplasm. FLT3 mutations frequently co-occurred with NPM1 and DNMT3A mutations (39%) and chromatin or RNA splicing gene mutations (15%), and were also associ¬ated with t(15;17) and t(6;9) translocations (35% and 80%, respectively).Patients with FLT3-ITD mutation are usually not cured with conventional chemotherapy [4]. They have higher induction death rate, a lower CR rate, increased risk of relapse, and adverse DFS, event-free survival, and OS [5].
Authors and Affiliations
Nahla A M Hamed
Keywords
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- EP ID EP567427
- DOI 10.26717/BJSTR.2017.01.000139
- Views 169
- Downloads 0
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